tbuckley/cabot-search huggingface dataset:
ALKBH5 activates FAK signaling through m6A demethylation in <i>ITGB1</i> mRNA and enhances tumor-associated lymphangiogenesis and lymph node metastasis in ovarian cancer
Authors: Rui Sun, Lin Yuan, Yi Jiang, Yicong Wan, Xiaolling Ma, Jing Yang, Guodong Sun, Shulin Zhou, Hui Wang, Jiangnan Qiu, Lin Zhang, Wenjun Cheng
Journal: Theranostics (2023)

Background: Lymph node (LN) metastasis is common in patients with epithelial ovarian cancer (EOC) and is associated with poor prognosis.Tumor-associated lymphangiogenesis is the first stage of LN metastasis.Research on lymphangiogenesis and lymph node metastases can help develop new anti-LN-targeted therapies.Aberrant N6-methyladenosine (m6A) modifications have been reported to be linked to LN metastasis in several cancers, however, their role in EOC lymphangiogenesis and LN metastasis remains unclear.Methods: m6A levels in EOC tissues with or without LN metastases were evaluated by dot blot analysis.Real-time polymerase chain reaction (PCR) and immunofluorescence were used to examine the expression of m6A-related enzymes.Additionally, in vitro and in vivo functional studies were performed to discover the importance of the AlkB homolog 5 (ALKBH5) gene in EOC lymphatic metastasis.To identify the downstream target genes regulated by ALKBH5, we performed RNA pulldown, RNA-binding protein immunoprecipitation-quantitative PCR, co-immunoprecipitation, m6A-modified RNA immunoprecipitation-quantitative PCR, and luciferase reporter assays.Results: m6A modification was reduced in ovarian cancers with LN metastases.ALKBH5 overexpression increased tumor-associated lymphangiogenesis and LN metastasis both in vitro and in vivo.ALKBH5 overexpression also reversed the m6A modification in ITGB1 mRNA and suppressed the YTHDF2 protein-mediated m6A-dependent ITGB1 mRNA degradation, which resulted in increased expression of ITGB1 and phosphorylation of the focal adhesion kinase (FAK) and Src proto-oncogene proteins, thereby increasing LN metastasis.Furthermore, hypoxia induced the expression of hypoxia inducible factor 1 subunit alpha, which increased ALKBH5 expression and enhanced LN metastasis in EOC. Conclusions:The ALKBH5/m6A-ITGB1/FAK signalling axis is important in ovarian cancer lymphangiogenesis and LN metastasis.Antibodies that block ITGB1 and FAK kinase-inhibitors are promising anti-metastatic agents.
Battles against aberrant KEAP1-NRF2 signaling in lung cancer: intertwined metabolic and immune networks
Authors: Ke Xu, Jie Ma, Sean R. R. Hall, Ren-Wang Peng, Haitang Yang, Feng Yao
Journal: Theranostics (2023)

The Kelch-like ECH-associated protein 1/nuclear factor erythroid-derived 2-like 2 (KEAP1/NRF2) pathway is well recognized as a key regulator of redox homeostasis, protecting cells from oxidative stress and xenobiotics under physiological circumstances.Cancer cells often hijack this pathway during initiation and progression, with aberrant KEAP1-NRF2 activity predominantly observed in non-small cell lung cancer (NSCLC), suggesting that cell/tissue-of-origin is likely to influence the genetic selection during malignant transformation.Hyperactivation of NRF2 confers a multi-faceted role, and recently, increasing evidence shows that a close interplay between metabolic reprogramming and tumor immunity remodelling contributes to its aggressiveness, treatment resistance (radio-/chemo-/immune-therapy) and susceptibility to metastases.Here, we discuss in detail the special metabolic and immune fitness enabled by KEAP1-NRF2 aberration in NSCLC.Furthermore, we summarize the similarities and differences in the dysregulated KEAP1-NRF2 pathway between two major histo-subtypes of NSCLC, provide mechanistic insights on the poor response to immunotherapy despite their high immunogenicity, and outline evolving strategies to treat this recalcitrant cancer subset.Finally, we integrate bioinformatic analysis of publicly available datasets to illustrate the new partners/effectors in NRF2-addicted cancer cells, which may provide new insights into context-directed treatment.
Kruppel-like factor 2 contributes to blood-spinal cord barrier integrity and functional recovery from spinal cord injury by augmenting autophagic flux
Authors: Zili He, Jiqing Du, Yu Zhang, Yitie Xu, Qian Huang, Qingwei Zhou, Min Wu, Yao Li, Xie Zhang, Hongyu Zhang, Yuepiao Cai, Keyong Ye, Xiangyang Wang, Yingze Zhang, Qi Han, Jian Xiao
Journal: Theranostics (2023)

Background: Increasing evidence suggests that acute traumatic spinal cord injury (SCI)-induced defects in autophagy and autophagy-lysosomal pathway (ALP) may contribute to endothelial barrier disruption following injury. Recently, Kruppel-like factor 2 (KLF2) was reported as a key molecular switch on regulating autophagy. Whether KLF2 coordinates endothelial endothelial ALP in SCI is not known. Methods: Genetic manipulations of KLF2 were performed in bEnd.3 cells and SCI model. Western blot, qRT-PCR, immunofluorescence staining and Lyso-Tracker Red staining, Evans blue dye extravasation, behavioral assessment via Basso mouse scale (BMS), electrophysiology and footprint analysis were performed. Results: In SCI, autophagy flux disruption in endothelial cells contributes to TJ proteins degradation, leading to blood-spinal cord barrier (BSCB) impairment. Furthermore, the KLF2 level was decreased in SCI, overexpression of which alleviated TJ proteins loss and BSCB damage, which improve motor function recovery in SCI mice, while knockdown of KLF2 displayed the opposite effects. At the molecular level, KLF2 overexpression alleviated the TJ proteins degradation and the endothelial permeability by tuning the ALP dysfunction caused by SCI and oxygen glucose deprivation (OGD). Conclusions: Endothelial KLF2 as one of the key contributors to SCI-mediated ALP dysfunction and BSCB disruption. KLF2 could be a promising pharmacological target for the management and treatment of SCI.
Dynamic white matter changes in recovered COVID-19 patients: a two-year follow-up study
Authors: Sihong Huang, Xianglin Zhou, Wei Zhao, Yanyao Du, Danhui Yang, Yijie Huang, Yanjing Chen, Huiting Zhang, Guang Yang, Jun Liu, Hong Luo
Journal: Theranostics (2023)

Background and purpose: Long COVID with regard to the neurological system deserves more attention, as a surge of treated patients are being discharged from the hospital. As the dynamic changes in white matter after two years remain unknown, this characteristic was the focus of this study. Methods: We investigated 17 recovered COVID-19 patients at two years after discharge. Diffusion tensor imaging, neurite orientation dispersion and density imaging were performed to identify white matter integrity and changes from one to two years after discharge. Data for 13 revisited healthy controls were collected as a reference. Subscales of the Wechsler Intelligence scale were used to assess cognitive function. Repeated-measures ANOVA was used to detect longitudinal changes in 17 recovered COVID-19 patients and 13 healthy controls after one-year follow-up. Correlations between diffusion metrics, cognitive function, and other clinical characteristics (i.e., inflammatory factors) were also analyzed. Results: Longitudinal analysis showed the recovery trends of large-scale brain regions, with small-scale brain region deterioration from one year to two years after SARS-CoV-2 infection. However, persistent white matter abnormalities were noted at two years after discharge. Longitudinal changes of cognitive function showed no group difference. But cross-sectional cognitive difference between recovered COVID-19 patients and revisited HCs was detected. Inflammation levels in the acute stage correlated positively with white matter abnormalities and negatively with cognitive function. Moreover, the more abnormal the white matter was at two years, the greater was the cognitive deficit present. Conclusion: Recovered COVID-19 patients showed longitudinal recovery trends of white matter. But also had persistent white matter abnormalities at two years after discharge. Inflammation levels in the acute stage may be considered predictors of cognition and white matter integrity, and the white matter microstructure acts as a biomarker of cognitive function in recovered COVID-19 patients. These findings provide an objective basis for early clinical intervention.
3,4-Dimethoxychalcone, a caloric restriction mimetic, enhances TFEB-mediated autophagy and alleviates pyroptosis and necroptosis after spinal cord injury
Authors: Haojie Zhang, Wenfei Ni, Gaoxiang Yu, Yibo Geng, Junsheng Lou, Jianjun Qi, Yituo Chen, Feida Li, Hantao Ye, Haiwei Ma, Hui Xu, Luying Zhao, Yuepiao Cai, Xiangyang Wang, Huazi Xu, Jian Xiao, Kailiang Zhou
Journal: Theranostics (2023)

Background: Caloric restriction mimetics (CRMs) mimic the favourable effects of caloric restriction (CR) and have been shown to have therapeutic effects in neuroinflammatory disease. However, whether CRMs improve the functional recovery from spinal cord injury (SCI) and the underlying mechanism of action remain unclear. In this study, we used the CRMs 3,4-dimethoxychalcone (3,4-DC) to evaluate the therapeutic value of CRMs for SCI. Methods: HE, Masson and Nissl staining; footprint analysis; and the Basso mouse scale were used to determine the functional recovery from SCI after 3,4-DC treatment. RNA sequencing was used to identify the mechanisms of 3,4-DC in SCI. Western blotting, qPCR and immunofluorescence were used to detect the levels of pyroptosis, necroptosis, autophagy and the AMPK-TRPML1-calcineurin signalling pathway. We employed a dual-luciferase reporter assay in vitro and applied AAV vectors to inhibit TFEB in vivo to explore the mechanism of 3,4-DC. Results: 3,4-DC reduced glial scar area and motor neuron death and improved functional recovery after SCI. RNA-sequencing results indicated that oxidative stress, pyroptosis, necroptosis, and autophagy may be involved in the ability of 3,4-DC to improve functional recovery. Furthermore, 3,4-DC inhibited pyroptosis and necroptosis by enhancing autophagy. We also found that 3,4-DC enhances autophagy by promoting TFEB activity. A decrease in the TFEB level abolished the protective effect of 3,4-DC. In addition, 3,4-DC partially regulated TFEB activity through the AMPK-TRPML1-calcineurin signalling pathway. Conclusions: 3,4-DC promotes functional recovery by upregulating TFEB-mediated autophagy and inhibiting pyroptosis and necroptosis after SCI, which may have potential clinical application value.
ATPase family AAA domain-containing protein 2 (ATAD2): From an epigenetic modulator to cancer therapeutic target
Authors: Jiahui Fu, Jin Zhang, Xiya Chen, Zhiying Liu, Xuetao Yang, Zhendan He, Yue Hao, Bo Liu, Dahong Yao
Journal: Theranostics (2023)

ATPase family AAA domain-containing protein 2 (ATAD2) has been widely reported to be a new emerging oncogene that is closely associated with epigenetic modifications in human cancers.As a coactivator of transcription factors, ATAD2 can participate in epigenetic modifications and regulate the expression of downstream oncogenes or tumor suppressors, which may be supported by the enhancer of zeste homologue 2.Moreover, the dominant structure (AAA + ATPase and bromine domains) can make ATAD2 a potential therapeutic target in cancer, and some relevant small-molecule inhibitors, such as GSK8814 and AZ13824374, have also been discovered.Thus, in this review, we focus on summarizing the structural features and biological functions of ATAD2 from an epigenetic modulator to a cancer therapeutic target, and further discuss the existing small-molecule inhibitors targeting ATAD2 to improve potential cancer therapy.Together, these inspiring findings would shed new light on ATAD2 as a promising druggable target in cancer and provide a clue on the development of candidate anticancer drugs.
Selected Articles from This Issue
Journal: Clinical Cancer Research (2023)

Shoushtari and colleagues report a pilot trial of ONCOS-102, a novel oncolytic adenovirus encoding GM-CSF, administered intratumorally either sequentially or in combination with pembrolizumab in patients with melanoma resistant to prior PD-1 blockade.Treatment was well tolerated.Objective responses were seen in 7 of 20 patients, and size reductions in noninjected lesions suggested local delivery of ONCOS-102 can drive a systemic anti-tumor effect.Serial biopsies of injected tumors at baseline, Week 3 (following ONCOS-102 and prior to pembrolizumab), and Week 9 (following ONCOS-102 and pembrolizumab) indicated that while most tumors experience CD8 þ and CD4 þ infiltration after ONCOS-102 injection, sustained infiltration at Week 9 was associated with clinical benefit.Future trials of ONCOS-102 and checkpoint inhibition are warranted in anti-PD-1-resistant melanoma.These findings suggest trials using viral agents in anti-PD-1-resistant disease should not solely rely on early onset of cytotoxicity to predict clinical response.
Quantification of REM sleep without atonia: A review of study methods and meta-analysis of their performance for the diagnosis of RBD
Authors: Monica Puligheddu, Michela Figorilli, Patrizia Congiu, Rosamaria Lecca, Elisa Casaglia, Ludovica Tamburrino, Riccardo Orrù, Federico Meloni, Raffaele Ferri
Journal: Sleep Medicine Reviews (2023)
Formalising social representation to explain psychiatric symptoms
Authors: Joseph M. Barnby, Peter Dayan, Vaughan Bell
Journal: Trends in Cognitive Sciences (2023)

Recent work in social cognition has moved beyond a focus on how people process social rewards to examine how healthy people represent other agents and how this is altered in psychiatric disorders. However, formal modelling of social representation has not kept pace with these changes, impeding our understanding of how core aspects of social cognition function, and fail, in psychopathology. Here, we suggest that belief-based computational models provide a basis for an integrated sociocognitive approach to psychiatry, with the potential to address important but unexamined pathologies of social representation, such as maladaptive schemas and illusory social agents.
Matrescence: lifetime impact of motherhood on cognition and the brain
Authors: Edwina R. Orchard, Helena J.V. Rutherford, Avram J. Holmes, Sharna D. Jamadar
Journal: Trends in Cognitive Sciences (2023)

Profound environmental, hormonal, and neurobiological changes mark the transition to motherhood as a major biosocial life event. Despite the ubiquity of motherhood, the enduring impact of caregiving on cognition and the brain across the lifespan is not well characterized and represents a unique window of opportunity to investigate human neural and cognitive development. By integrating insights from the human and animal maternal brain literatures with theories of cognitive ageing, we outline a framework for understanding maternal neural and cognitive changes across the lifespan. We suggest that the increased cognitive load of motherhood provides an initial challenge during the peripartum period, requiring continuous adaptation; yet when these demands are sustained across the lifespan, they result in increased late-life cognitive reserve.
Re: Adjuvant Atezolizumab Versus Placebo for Patients with Renal Cell Carcinoma at Increased Risk of Recurrence Following Resection (IMmotion010): A Multicentre, Randomised, Double-blind, Phase 3 Trial
Authors: Zine-Eddine Khene, Delphine Borchiellini, Karim Bensalah
Journal: European Urology (2023)
A Transgender Patient with Prostate Cancer: Lessons Learnt
Authors: Khobe Chandran, Rafael Grochot, Maria de Los Dolores Fenor De La Maza, Wei Yuan, Bora Gurel, Susana Miranda, Alec Paschalis, Ruth Riisnaes, Ines Figueiredo, Denisa Bogdan, Adam Sharp, Suzanne Carreira, Johann S. de Bono
Journal: European Urology (2023)
Genetic Risk Prediction for Prostate Cancer: Implications for Early Detection and Prevention
Authors: Tyler M. Seibert, Isla P. Garraway, Anna Plym, Brandon A. Mahal, Veda Giri, Michelle F. Jacobs, Heather H. Cheng, Stacy Loeb, Brian T. Helfand, Rosalind A. Eeles, Todd M. Morgan
Journal: European Urology (2023)
Urethritis Without Skin Lesions as the Primary Manifestation of Mpox Virus Infection
Authors: Laurens Liesenborghs, Veerle Huyst, Christophe Van Dijck, Jojanneke Rutgers, Irith De Baetselier, Chris Kenyon, Marjan Van Esbroeck, Koen Vercauteren
Journal: European Urology (2023)
Microbiota-dependent proteolysis of gluten subverts diet-mediated protection against type 1 diabetes
Authors: Matthew C. Funsten, Leonid A. Yurkovetskiy, Andrey Kuznetsov, Derek Reiman, Camilla H.F. Hansen, Katharine I. Senter, Jean Lee, Jeremy Ratiu, Shiva Dahal-Koirala, Dionysios A. Antonopoulos, Gary M. Dunny, Ludvig M. Sollid, David Serreze, Aly A. Khan, Alexander V. Chervonsky
Journal: Cell Host & Microbe (2023)
Education for planetary health
Authors: None The Lancet Planetary Health
Journal: The Lancet Planetary Health (2023)

Making change is often difficult, from individuals seeking healthier lifestyles, start-up companies struggling to cope with rapid growth, to national and international commitments to reduce greenhouse gas emissions and halt biodiversity loss there is a learning journey. Even in the simplest case of individuals following an established syllabus learning is nontrivial, requiriang time, energy, self-awareness, and discipline. When learning is scaled up to the level of organisations the challenges are much greater because there is usually no established learning pathway to follow and a whole suite of legal, procedural, and cultural factors create organisational inertia that is resistant to change.
Recommendations for defining preventable HIV-related mortality for public health monitoring in the era of Getting to Zero: an expert consensus
Authors: Sara E Croxford, Veronique Martin, Sebastian B Lucas, Robert F Miller, Frank A Post, Jane Anderson, Vanessa J Apea, David Asboe, Garry Brough, David R Chadwick, Simon Collins, Helen Corkin, Gillian Dean, Valerie C Delpech, Maka Gogia, Deborah Gold, Anna Kafkalias, Marilena Korkodilos, Justyna D Kowalska, Jacqueline Lindo, Jens D Lundgren, Lucy Lynch, Esteban Martinez, Niall McDougall, Sarah North, Juergen K Rockstroh, Caroline Sabin, Maria Vidal-Read, Laura J Waters, Ann K Sullivan
Journal: The Lancet HIV (2023)
Impaired motor development in children with familial high risk of schizophrenia or bipolar disorder and the association with psychotic experiences: a 4-year Danish observational follow-up study
Authors: Birgitte Klee Burton, Mette Falkenberg Krantz, Lene Theil Skovgaard, Julie Marie Brandt, Maja Gregersen, Anne Søndergaard, Christina Bruun Knudsen, Anna Krogh Andreassen, Lotte Veddum, Sinnika Birkehøj Rohd, Martin Wilms, Camilla Tjott, Carsten Hjorthøj, Jessica Ohland, Aja Greve, Nicoline Hemager, Vibeke Fuglsang Bliksted, Ole Mors, Kerstin Jessica Plessen, Anne Amalie Elgaard Thorup, Merete Nordentoft
Journal: The Lancet Psychiatry (2023)
Editorial Board
Authors: Zuhair Ballas, Iowa City, Iowa Deputy, David Huston, Rachel Miller, New York, N Associate, Andrea Apter, Leonard Philadelphia, Nashville Bacharier, Claus Bachert, Joshua Boyce, Javier Chinen, Raif Geha, Johann Gudjonsson, Ann Arbor, Mich Kenji Kabashima, Corinne Keet, Chapel Hill, Carole Ober, Wanda Phipatanakul, Harald Renz, Marburg Germany, Marc Rothenberg, Cincinnati Ohio, Hirohisa Saito, Stefan Vieths, Langen Germany, Stephan Weidinger, Ioana Agache, Lara Akinbami, Amy Klion, Hans Oettgen, Nikolaos Papadopoulos, Ian Pavord, Rob Aalberse, M Cecilia Berin, Janet Chou, Francesca Levi-Schaffer, Richard Looney, Mohamed Shamji, Kathleen Barnes, Alain Fischer, Peter Gergen
Journal: Journal of Allergy and Clinical Immunology (2023)
Glutamatergic neurotransmission: A potential pharmacotherapeutic target for the treatment of cognitive disorders
Authors: Pratik Chakraborty, Abhijit Dey, Abilash Valsala Gopalakrishnan, Kumari Swati, Shreesh Ojha, Anand Prakash, Dhruv Kumar, Rashmi K. Ambasta, Niraj Kumar Jha, Saurabh Kumar Jha, Saikat Dewanjee
Journal: Ageing Research Reviews (2023)
Inhibitory top-down projections from zona incerta mediate neocortical memory
Authors: Anna Schroeder, M. Belén Pardi, Joram Keijser, Tamas Dalmay, Ayelén I. Groisman, Erin M. Schuman, Henning Sprekeler, Johannes J. Letzkus
Journal: Neuron (2023)

Top-down projections convey a family of signals encoding previous experiences and current aims to the sensory neocortex, where they converge with external bottom-up information to enable perception and memory. Whereas top-down control has been attributed to excitatory pathways, the existence, connectivity, and information content of inhibitory top-down projections remain elusive. Here, we combine synaptic two-photon calcium imaging, circuit mapping, cortex-dependent learning, and chemogenetics in mice to identify GABAergic afferents from the subthalamic zona incerta as a major source of top-down input to the neocortex. Incertocortical transmission undergoes robust plasticity during learning that improves information transfer and mediates behavioral memory. Unlike excitatory pathways, incertocortical afferents form a disinhibitory circuit that encodes learned top-down relevance in a bidirectional manner where the rapid appearance of negative responses serves as the main driver of changes in stimulus representation. Our results therefore reveal the distinctive contribution of long-range (dis)inhibitory afferents to the computational flexibility of neocortical circuits.
Exercise Training Improves Exercise Capacity in Preterm-Born Adults: Lessons for Clinical Trials?
Authors: Kara N. Goss, Andrew T. Lovering
Journal: American Journal of Respiratory and Critical Care Medicine (2023)

"Exercise Training Improves Exercise Capacity in Preterm-Born Adults: Lessons for Clinical Trials?." American Journal of Respiratory and Critical Care Medicine, 0(ja), pp. –
The World Organization of Family Doctors Air Health Train the Trainer Program: lessons learned and implications for planetary health education
Authors: Alice McGushin, Enrique Falceto de Barros, Mayara Floss, Yousser Mohammad, Achiri E Ndikum, Christophe Ngendahayo, Peter A Oduor, Sadia Sultana, Rachel Wong, Alan Abelsohn
Journal: The Lancet Planetary Health (2023)
Embedding Indigenous knowledges and voices in planetary health education
Authors: Gabrielle Brand, Steve Wise, Gitanjali Bedi, Rosalie Kickett
Journal: The Lancet Planetary Health (2023)

Internationally, the health-care sector has been slower than many other sectors in reducing its carbon emissions and broader environmental footprint. Incrementally, tertiary education institutions are changing their focus to integrate environmental and social objectives, including planetary health, into teaching, research, and how the campus is operated. Planetary health and sustainable health-care are emerging topics in the education of health professionals. However, they have largely been limited to specific knowledge rooted in western epistemology with ad hoc curricula that do not consider the complex interdependence of ecosystems and human health. Because of the need to prepare the current and future health-care workforce for planetary consciousness and related practices, in this Personal View we provide an innovative case study that uses Indigenist health humanities (eg, narrative portraiture) and arts-based education strategies to offer a different way of seeing, knowing, and understanding planetary health. Embedding Indigenous knowledges and voices into planetary health education is an important first step in decolonising learning in health professional education.